20-(lower aliphatic hydrocarbon)-delta17(20)-pregnen-21-oic acids



United States Patent 3,158,625 ZS-(LQWER ALEHATIC HYDROCON)- A -PREGNEN-21-0IC ACIDS Albert Bowers and Pierre Qrabh, Mexico City, Mexico, assignors to Syntax Corporation, Panama, Panama, a corporation of Panama No Drawing. Filed lane 17, 1963, Ser. No. 283,497 20 Qlairns. (Cl. 260-3971) This invention relates to novel cyclopentanopolyhydrophenanthrene derivatives and to processes for their preparation. More particularly, this invention relates to novel 20-(lower aliphatic hydrocarbon)-A -pregnen-21-oic acids and derivatives thereof represented by the general formulas:

In these formulas, R and R each represent hydrogen or an acyl group of less than 12 carbon atoms; R represents hydrogen, a lower alkyl group, e.g., methyl, ethyl, propyl, and the like, and especially methyl, or an alkali metal, e.g., lithium, sodium or potassium; R represents a saturated or unsaturated, straight or branchedchain aliphatic hydrocarbon radical containing 1 to 8 carbon atoms, inclusive, such as methyl, ethyl, propyl, isopropyl, butyl, isohexyl (4-methylpentyl), 3,4-dimethylpentyl, 3- ethyl-4-methylpentyl, vinyl, isohexenyl(4-methylpent-3- enyl), and the like; R represents OL-hYdl'OXYlfl-hydroxyl, their tetrahydropyranyl ethers, or a keto group; R represents hydrogen or a lower alkyl group, especially methyl; R represents a lower alkyl group, particularly methyl, and Z represents a saturated linkage (single bond) or a double bond at the 4,5-position.

Wherever used, the symbol 5 indicates that singly bonded substituents at the 3-, 4- and l6-positi0ns of the steroid nucleus can be present in either the a or the ,8-configuration, while substituents at the 20-position can be either cisor trans[20(cis) or 20(trans)] with respect to the methyl group in the ls-position.

The novel ZO-(lower aliphatic hydrocarbon-A pregnen-Zl-oic acids and derivatives thereof represented by formulas A, B and C above are antibiotic agents, and more particularly antibacterial and antifungal agents having good'systemic activity when administered orally 3,158,625 Patented Nov. 24, 1964 'or parenterally. They also have good antibiotic activity when applied topically.

The compounds of the present invention can be prepared by processes Which can be depicted as follows:

The acyl and acyloxy groups referred to herein are derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, or aromatic, and may be substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentyl propionate, aminoacetate, and fl-chloropropionate.

In these formulas R, R R R R R R and Z have the same meaning as set forth hereinabove for formulas A, B and C, with the exception that in certain cases R can also represent a tetrahydropyranyl radical.

In practicing the process outlined in the above reaction scheme, the starting material, 160;, l7a-epoxy-A pregnen-Elfi-ol-ZO-one (I; R=H), or a 3-acylate, e.g., the 3-acetate, thereof (1; R=acyl), is treated according to the Huang-Minlon modification of the Wolfi-Kishner method, i.e., with hydrazine hydrate in the presence of potassium hydroxide in ethylene glycol-water suspension, to produce the corresponding A -pregnadiene-3fl, 16oL-dl0l or the 3-acylate thereof (ll). This reaction is preferably carried out at reflux temperature for about 45 minutes and then at 200 C. for about 2 hours, but it can also be carried out at room temperature by using hydrazine hydrate together with acetic acid, preferably in the presence of a lower alkanol, e.g., ethanol.

Treatment of the thus obtained A -pregnadiene (II) with manganese dioxide or 2,3-dichloro-5,6-dicyano- A -benzoquinone, preferably in an inert organic solvent such as chloroform, dioxane, or the like, generally at room temperature for about 18 hours, results in the cor-' responding A -pregnadien-3,8-01-16-one or its 3-acylate (III).

This 16-one (III) is then reacted with approximately 1 molar equivalent of bromine, preferably in the presence of a catalytic amount of an amine, such as pyridine and the like, to give the corresponding 5c,65-dibromo derivative (IV) which is then treated with approximately 1 molar equivalent of N-iodosuccinirnide, under conventional conditions, to produce the corresponding 5a,6,fidibromo-Zl-iodo derivative (V). This ll-iodo derivative (V) is then treated with sodium iodide, under conventional conditions, to remove the bromine from the 5- and 6-positions, thus restoring the 5,6-double bond and resulting in the formation of the corresponding A -2l-iodo derivative (VI), which in turn is treated with a potassium acylate, e.g., potassium acetate, preferably in acetone at reflux temperature, to yield the corresponding d pregnadienefil1-diol-l6-one 2l-acylate or the corresponding 3,2l-diacylate (VII).

The 2l-acylate or the 3,2l-diacylate (VII), upon treatment with approximately 3 molar equivalents of a lower aliphatic hydrocarbon magnesium halide wherein the lower aliphatic hydrocarbon moiety contains from 1 to 8 carbon atoms, inclusive, e.g., methyl magnesium bromide, affords the corresponding 20-(lower aliphatic hydrocarbon)-A -pregnene-3;3,2l-diol-l6-one (VIII; R=H). This reaction is carried out in the presence of cuprous chloride, preferably using tetrahydrofuran as a solvent and reacting at a temperature of about 28 C. for about 2 hours. The 3-hydroxy group of the resulting 3,8,21-diol (VIII; R=H) is then selectively acylated by first treating the diol with triphenyimethyl chloride, using conven tional conditions, reacting the resulting Zl-triphenylmeth- Eyl ether with a carboxylic acid anhydride, e.g., acetic anhydride, and finally hydrolyzing the ZI-triphenylrnethyl ether group, preferably under acidic conditions, e.g., using hydrogen bromide in acetic acid.

The thus obtained 3-acylate (VIII; R=aeyl), is then oxidized, preferably with l ones reagent at room temperature, using an amount of the reagent sufiicient to permit the color thereof to persist in the reaction mixture at least 10 minutes, to produce the corresponding 3-acyl-ate of the ZtJ-(lower aliphatic hydrocarbon)--A -pregnen-3j8-oll6-one-2l-oic acid (IX; R=acyl, R =H). This 2l-oic acid is reacted with a diazoflower) alkane, e.g., diazomethane, preferably in methanol at room temperature for about 10 minutes, to yield the corresponding 21-oic acid lower alkyl ester (IX; R=acyl, R =lower alkyl). Bromination of this Zl-oic acid lower alkyl ester with approximately one and one-half molar equivalents of bromine, preferably in the presence of hydrogen bromide, yieidsthe correspondwhich, upon treatment with an excess of sodium iodide at reflux temperature, preferably using methyl ethyl ketone as a solvent, results in the corresponding S-acylate of the ZG-(lower aliphatic hydrocarbon)-l7a-brorno-A -pregnen- 3,8-ol-l6-one-2l-oic acid lower alkyl ester (Xi; R acyl,

R =lower alkyl). This 170c-bIOm0 derivative in dehydrobrominated, preferably using calcium chloride in dimethylformamide at reflux temperature for about 45 minutes, following which the resulting product is chromatographed to separate the 3-acylates of the 20 [cis]-(lower aliphatic hydrocarbon)-A -pregnadien-3,8-ol-l6-one-21-oic acid lower alkyl ester and the corresponding 20 [trans] derivative (XII; R=acyl, R =lower alkyl).

Reduction of these 20 [cis]- and [transl-derivatives (XII) with a double metal hydride, e.g., sodium borohydride, prefer-ably in a water-free methanol-tetrahydrofuran solution, followed by chromatographic separation, yields the 3-acylates of the corresponding 2()[cis]- and 20{trans]-(lower aliphatic hydrocarbon)-A -pregnadifi6-3fi,16oc-di0l-Z1-Oi acid lower alkyl esters and their lSB-hydroxy isomers (XIII; R=acyl, R =lower alkyl,

=OH). Treatment of these l6-hydroxy derivatives with dihydropyrane in the presence of p-toluenesulfonic acid, e.g., at room temperature for 4 days, affords the corresponding l6-tetrahydropyranyloxy derivatives (XIII; R=acyl, :lovver alkyl, R :tetrahydropyranyloxy). Conventional saponification of these l6-tetrahydropyranyloxy derivatives results in the corresponding l6-tetrahydropyranyl ethers of the 20[cis]- and 20'[trans]-(lower aliphatic hydrocarbon)-A -pregnadiene-3/3, 16oc-di0l-2 1- oic acids and their l6fi-hydroxy isomers (Xlll; R=H, R =H, R :tetrahydropyranyloxy).

Treatment of the thus obtained 35,16 and IGfl-diols under conventional Oppenauer oxidation conditions results in the corresponding A -3-keto derivatives (XIV; R =H, R =tetrahydropyranyk Z=a double bond). Conventional acid hydrolysis of these A -3-keto-l6-tetrahydropyranyloxy derivatives yields the corresponding A -3-keto- 16aand l6fl-hydroxy derivatives (XIV; R =H, R =H, Z=a double bond). These A -3-keto-l6-hydr0xy derivatives, when treated with a lower alkyl iodide, e.g., methyl iodide, in the presence of potassium t-butoxide in solution in t-butanol, preferably at reflux temperature for about 3 hours, yield the corresponding 4-lower alkyl-l6-hydroxy- A -3-keto derivatives (XV; R =l-I, R =H, R =lower alkyl, Z=a double bond). Hydrogenation of these 4- lower alkyl-l6-hydroxy-A -3-keto derivatives with approximately 1 molar equivalent of hydrogen, preferably using a 5% palladium-on-charcoal catalyst, aflords the corresponding ie-lower alkyl-ZO [cis]- and 20[trans]-(lower aliphatic hydrocarbon) -A -a1lopregnen-16-ol 3- one 21-oic acids (XV; R =H, R =H, R =lower alkyl, 2: a saturated linkage), which, in turn, give the corresponding 4u-lower alkyl isomers when treated with a base, e.g., sodium hydroxide, under conventional conditions.

Reduction of the thus obtained 4Cc-IOW6I' alkyl isomers with a double metal hydride, e.g., sodium borohydride, results in the corresponding 4a-lower alkyl-20[cis]- and 20[trans]-(lower aliphatic hydrocarbon)A -pregnene- 33,16-diol-21-oic acids (XVI; R=H, R =H, R :H, R =lower alkyl). Reduction of the same 4oc-1OW6I alkyl isomers with non-pyrophoric Raney nickel rather than a double metal hydride, preferably in ethanol at reflux temperature for about 5 hours, results in the corresponding 4oc1OWCI alkyl-2O [cis]- and 20 [trans]-(lower aliphatic hydrocarbon)-A -pregnene-3 u,16-di01 21 oic acids (XVI; R=H, R =H, R =H, R =lower alkyl).

The novel ZO-(lower aliphatic hydrocarbon)-A -pregnen-Zl-oic acids and derivatives thereof of the present invention having a free secondary hydroxyl group, e.g., at the 3- or the lo-position, can be acetylated by conventional methods, e.g., by using a suitable acylating agent, such as a carooxylic acid, or a chloride or anhydride thereof, of the type mentioned hereinabove, in the presence of pyridine.

Similarly, the compounds of the present invention having a free carboxyl group attached to the carbon atom at the 20-position, e.g., compounds XII-XVI, inclusive, as shown hereinabove, wherein R =H can be converted to the corresponding 2l-oic acid lower alkyl esters by conventional esterification with a diazo (lower) alkane, e.g., diazomethane and the like. The free carboxyl compounds of the present invention can also be converted to the corresponding alkali metal salt derivatives by reaction with approximately 1 molar equivalent of an alkali metal hydroxide, e.g., sodium or potassium hydroxide, under conventional conditions.

Treatment of the A -3-keto derivatives of the present invention, i.e., compounds XIV and XV as shown hereinabove, with approximately 1 molar equivalent of hydrogen, preferably using a hydrogenation catalyst such as 5% palladium-on-charcoal, aiiords the corresponding 3-keto- Soc-COIIIPOllHdS (XTV and XV; Z=saturated linkage).

The following working examples serve to illustrate, but are not intended to limit the scope of the present invention:

Example I A mixture of 1 g. of the known 16a,17c-epoxy-A pregnen-Bfiwl-ZO-one, 2 g. of hydrazine hydrate, 1.0 cc. of acetic acid and 10 cc. of ethanol were stirred at room temperature for 30 minutes. Then water was added and the product isolated by extraction with methylene chloride. Recrystallization of the residue obtained after evaporation of the solvent from acetone-hexane afforded A -pregnadiene-3fi,16u-dio1 (Compound No. 1).

Example 11 1 g. of Compound No. 1 in 100 cc. of chloroform, distilled from calcium chloride, was oxidized by stirring for 18 hours at room temperature with 10 g. of freshly precipitated manganese dioxide. The inorganic material was filtered, Washed with hot chloroform and the solution evaporated. Recrystallization from acetone-hexane gave A -pregnadien-3fi-ol-16-one (Cpd. No. 2).

Example HI A solution of 8 g. of Cpd. No. 2 in 100 cc. of chloroform containing a few drops of pyridine was cooled to 0 C. and slowly treated under stirring with a cooled solution of bromine in chloroform containing 1.05 molar equivalents of bromine. The mixture was allowed to reach room temperature, the excess of bromine was removed by fiushing with dry air and the solution was washed with 5% aqueous sodium bicarbonate solution and subsequently with water, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of the residue from methanolbenzeue afiorded 5a,6,8-dibronze-A -pregnen-3fl-ol-16-one. 4.2 g. of the latter compound in 200 cc. of carbon tetrachloride was refluxed with 2.7 g. of N-iodo-succinimide for 1 /2 hours. The mixture was filtered to eliminate the succinimide that is formed during the reaction. The filtrate was evaporated to dryness under reduced pressure. Recrystallization from methylene-chloride-hexane gave 5a,6fl-dibromo-21- iodo-A -pregnadienfl-ol-16-one.

A mixture of 2 g. of the latter compound, 2 g. of sodium iodide and 50 cc. of methyl ethyl ketone was refluxed for 8 hours. It was then cooled, poured into water and extracted with ethyl acetate. The organic extract was washed with aqueous sodium bisulfite solution, water, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of the residue from acetonehexane yielded 21-iodo-A -pregnadien-SB-ol-l6-one (Cpd. No. 3). This compound was mixed with cc. of acetone and 12 g. of recently fused potassium acetate and the mixture was refluxed for 8 hours, concentrated to a small volume, diluted with water and extracted with ethyl acetate; the extract was washed with water, dried over anhydrous sodium sulfate and concentrated until crystallization started. The precipitate was collected and crystallized from methanol-water, thus yielding M pregnadiene-3B,21-diol-16-one 21-acetate (Cpd. No. 4).

Example IV To a mixture of 1 g. of 11 -pregnadiene-3,8,2l-diol- Example V The Compound No. 4 was treated according to Example IV, except that methyl magnesium bromide was substituted by ethyl magnesium bromide, vinyl magnesium bromide, isohexyl magnesium bromide and 4-methyl-pent-3- enyl magnesium bromide thus yielding respectively:

Cpd. No.: (6) ZO-ethyl-A pregnene-3,6,21-diol-l6-one, (7) 20-vinyl-A -pregnene-3{3,21-diol-16-one, (8) 2G-isohexyl-M-pregnene-35,21-diol-16-one, (9) 20- 4'-methyl-pent-3 -enyl) -A -pregnene-3 13,2 l dioll6-one.

Example VI A mixture of 1 g. of Compound No. 5, 3 g. of triphenylmethyl chloride and 15 cc. of pyridine was heated on a steam bath for 2 hours, then it was cooled to 5 C. and 2 cc. of acetic anhydride were added. The resulting mixture was kept at the same temperature for 24 hours, then it was poured into ice-water and the resulting precipitate collected by filtration and dried. The dry solid was mixed thoroughly with 20 cc. of acetic acid and there were added 3 cc. of a saturated solution of hydrogen bromide in acetic acid. The resulting mixture was stirred for 3 minutes, then poured into ice water and the formed precipitate collected by filtration, washed with water, dried and crystallized from acetone-hexane, thus yielding 20- methyl-M-pregnene-BBJ1-diol-16-one 3-acetate (Cpd. No. 10).

The Compounds Nos. 6 to 9, inclusive, were treated by the same procedure, thus affording respectively:

Cpd. No.:

( 1 1 20-ethyl-A -pregnene-35,21-diol-16-one B-acetate,

(12) 20-vinyl-A -pregnene-3 {3,21-diol-16-one 3-acetate,

( 13) 20-isohexyl-M-pregnene-S5,21-dio1-16-one 3-acetate,

(14) 20-(4'-methyl-pent 3-enyl) -A -pregnene-3 {3,21-dioll6-one 3-acetate.

Example VII A solution of 1 g. of Compound No. 10 in 10 cc. of acetone was cooled to C. and treated under an atmosphere of nitrogen and with stirring, with a solution of 8 N chromic acid (prepared by mixing 26 g. of chromium trioxide with 23 cc. of concentrated sulfuric acid and diluting with water to 100 cc.), until the color of the reagent persisted in the mixture for 10 minutes. It was stirred for minutes further at 0-5 C. and diluted with water. The precipitate was colleced, washed with water and dried under vacuum, thus affording a crude product which upon recrystallization from acetone-hexane gave the 3-acetate of 2O-methy1-A -pregnen-3B-ol-16-one-21-oic acid (Cpd. No. 15).

The Compounds Nos. 11 to 14, inclusive, were treated following the latter procedure, thus furnishing respectively:

Cpd. No.:

(16) The B-acetate of 20-ethyl-A -pregnen-3;3-ol-16-0ne- 2l-oic acid,

21-oic acid,

3 (18) The 3-acetate of ZO-isohexyl-M-pregnen-3Bol-16- one 21-oic acid, (19) The 3-acetate of 2O-(4-methyl-pent-3'-enyl)-A pregnen-3[3-ol-l6-one-21-oic acid.

Example VIII To a mixture of 1 g. of Compound No. 15 and 50 cc. of methanol was added an ether solution of diazomethane, containing 500 mg. of the latter. The resulting mixture was kept at room temperature for ten minutes, then it was treated with a few drops of acetic acid to decompose the excess reagent, and evaporated to dryness. The residue was crystallized from acetone-hexane, thus yielding the 3-acetate of the 20-rnethyl-M-pregnen-Iifl-ol-l6-one- 2l-oic acid methyl ester (Cpd. No. 20).

The Compounds Nos. 16 to 19, inclusive, were treated following the same procedure thus affording respectively:

Cpd. No.:

(21) The B-acetate of the 2O-ethyl-A -pregnen-3fi-ol-l6- one-21-oic acid methyl ester,

(22) The 3-acetate of the 20-vinyl-A -pregnen-3fl-ol-16- one-21-oic acid methyl ester.

(23) The 3-acetate of the ZO-isohexyl-M-pregnen-313-01- 16-one-21-oic acid methyl ester,

(24) The S-acetate of the 20-(4'-methyl-pent-3'-enyl)- A -pregnen-3fi-ol-l6-one 2l-oic acid methyl ester.

Example IX A solution of 5 g. of Compound No. 20 in 100 cc. of acetic acid was treated with a few drops of hydrogen bromide in acetic acid and subsequently dropwise and with stirring, with a solution of 2.2 molar equivalents of bromine in 50 cc. of acetic acid. After all the bromine had been consumed, water was added, the formed precipitate filtered, washed with water to neutral and dried under vacuum. Recrystallization from acetone-hexane yielded the S-acetate of the ZO-methyl-Sa, 6,8, 17a-tribromo-pregnanp-ol-16-one-21-oic acid methyl ester (Cpd. No. 25).

The Compounds Nos. 21 and 23 were treated exactly by the above procedure, Compounds Nos. 22 and 24, were treated in accordance with the above method, except that 3.3 molar equivalents of bromine were used instead of 2.2 molar equivalents, thus being respectively obtained:

Cpd. No.:

(26) The 3-acetate of the 20-ethyl-5a,6fi,17a-tribromopregnan-3fi-ol-16-one-2l-oic-acid methyl ester,

(27) The 3-acetate of the 20-isohexyl-5a,6,17 oc-lrib101210 pregnan-3 8-ol-l6-one-2l-oic-acid methyl ester,

(28) The B-acetate of the 20-(1',2-dibromoethyl)-5e:,6fi, 17a-trihromo-pregnan-3Q-ol-16-one-2l-oic acid methyl ester,

(29) The 3-acetate of the 20-(3',4'-dibrorno-4'-methylpentyl)-5 x,6f3,17a-tribromo-pregnan -o1-16-one-21- oic acid methyl ester.

Example X A mixture of 2 g. of Compound No. 25, 2 g. of sodium iodide and cc. of methyl ethyl ketone was refluxed for 8 hours. It was then cooled, poured into water and extracted with ethyl acetate. The organic extract was washed with aqueous sodium bisulfite solution, water, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of the residue from acetoneexane yielded the S-acetate of the 20-methyl-17u-bromo- A -pregnen-3fi-ol-l6-one-21-oic acid methyl ester (Cpd. No. 30).

The Compounds Nos. 26 to 29, inclusive, were treated according to the same procedure, thus yielding respectively:

Cpd. No.:

(31) The 3-acetate of the 20-ethyl-l7u-bromo-A -pregnen- 3[3-ol16-one-21-oic acid methyl ester,

(32) The 3-acetate of the 20-isohexyl-17ot-bromo-A pregnen-Sfl-ol-l6-one-21-oic acid methyl ester,

(33) The 3-acetate of the 20-vinyl-17a-bromo-A -pregnen-3fi-ol-16-one-21-oic acid methyl ester,

(34) The 3-acetate of the 20-(4-methyl-pent-3'-enyl) 17a-bromo-A -pregnen-3fi-ol-l6-one-2l-oic acid methyl ester.

Example XI 2 g. of Compound No. 30 in 40 cc. of cold dimethyl formamide was added over minutes to a suspension of 5 g. of finely divided calcium carbonate in 15 cc. of refluxing dimethylformamide. The mixture was refluxed for 30 minutes further, cooled and filtered. The filtrate was diluted with water and extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid, water, aqueous sodium bicarbonate solution and water, then dried over anhydrous sodium sulfate and evaporated to dryness. Silica gel chromatography of the residue and recrystallization of the eluted fractions afforded the 3- acetate of the 2t)-[cis]-methyl-A -pregnadien-3t3-ol- 16-one-21-oic acid methyl ester (Cpd. No. 35) and the 3- acetate of the 20-[trans]-methyl-A -pregnadien-35 ol-16-one-2l-oic acid methyl ester (Cpd. No. 36).

Upon treatment under exactly the above conditions, Compound No. 31 yielded: The 3-acetate of the 20-[cis]- ethyl-A -pregnadien-3fi-ol-16-one 21 oic acid methyl ester (Cpd. No. 37) and the 3-acetate of the 20- [trans]-ethyl-A -pregnadien-3B-ol 16 one-21- oic acid methyl ester (Cpd. No. 38);

Compound No. 32 gave: The 3-acetate of the 20-[cis] isohexyl-A -pregnadien-3fi-ol-l6-one 21 oic'acid methyl ester (Cpd. No. 39) and the 3-acetate of the 20-[trans]-isohexyl-A -pregnadien-3,8-ol 16 0ne 21-oic acid methyl ester (Cpd. No. 40);

Compound No. 33 afforded: The 3-acetate of the 20- [cis] -vinyl-A -pregnadien-3[3-ol-16-one-21-oic acid methyl ester (Cpd. No. 41) and the 3-acetate of the 20- [trans]-vinyl-A -pregnadien-3 8-ol-16-one 21-oic acid methyl ester (Cpd. No. 42).

Compound No. 34 furnished: The 3-acetate of the 20- [cis] (4' methyl-pent-3-enyi) A pregnadien- 3fi-ol-16-one-21-oic acid methyl ester (Cpd. No. 43) and the 3-acetate of the 20-[trans]-(4-methylpent- 3-enyl)-A -pregnadien-3;3-ol-16-one 21 oic acid (Cpd. No. 44).

Example XII A solution of 2 g. of sodium borohydride in cc. of methanol was added with stirring to a solution of 2 g. of Compound No. in cc. of tetrahydrofuran. The mixture was kept at room temperature for 3 hours, the excess reagent was decomposed by addition of acetic acid, the resulting solution concentrated to small volume in vacuo and diluted with Water. The product was extracted with ethyl acetate, the extract Washed with water, dried and evaporated. Chromatography of the residue and crystallization of the solid fractions from acetonehexane gave the 3-acetate of the 20-[cisJ-methyl-A pregnadiene3,8,l6rx-diol-21-oic acid methyl ester (Cpd. N0. 45) and the S-acetate of the 2O-[cis]-methyl-A pregnadiene-3B,16B-diol-21-oic acid methyl ester (Cpd. No. 46).

The Compounds Nos. 36 to 44, inclusive, were treated by the above procedure, thus being respectively produced:

Cpd. No.2

(47) The 3-acetate of the ZO-[trans]-methyl-A pregnadiene-3fi,165-diol-21-oic acid methyl ester,

(48) The S-acetate of the 20-[trans]-methyl-A pregnadiene-3B,16ot-diol-21-oic acid methyl ester,

(49) The 3-acetate of the ZO-[cis]-ethyl-A -pregnadiene-3,8,16,8-diol-21-oic acid methyl ester,

(50) The S-acetate of the 2O-[cis]-ethyl-A -pregnadieue-3,8,16a-diol-21-oic acid methyl ester,

(51) The 3-acetate of the 2O-[trans]-ethyl-A (52) The 3-acetate of the 20-[trans]-ethyl-A pregnadiene-B/S,16a-diol-2l-oic acid methyl ester,

(53) The 3-acetate of the 20-[cis1-isohexy1-A pregnadiene-3,8,16,6-dio1-21-oic acid methyl ester,

(54) The 3-acetate of the 20-[cis]-isohexyl-A pregnadiene-3f3,16a-diol-21-oic acid methyl ester,

(55) The 3-acetate of the ZO-[trans]-isohexyl-A pregnadiene-Sfi,16f3-diol-2l-oic acid methyl ester,

(56) The 3-acetate of the 2O-[trans]-isohexyl-A pregnadiene-3,B,l6et-diol-2l-0ic acid methyl ester,

(57) The 3-acetate of the 20-[cis] -vinyl-A -pregnadiene-3fi,16B-diol-21-oic acid methyl ester,

(58) The 3-acetate of the 20-[cis]-vinyl-A -pregnadiene-3/3,16et-diol-21-oic acid methyl ester,

(59) The 3-acetate of the 20-[trans]-vinyl-A pregnadiene-3/3,16,8-diol-21-oic acid methyl ester,

(60) The S-acetate of the 20-[trans]-viny1-A pregnadiene-3B,16a-diol-21-oic acid methyl ester,

(61) The 3-acetate of the 20-[cis]-(4'-methyl-pent-3'- enyl) -A -pregnadiene-3p,16,6-diol-21-oic acidmethyl ester,

(62) The 3-acetate of the ZO-[cis]-(4'-methyl-pent-3'- enyl)-A -pregnadiene-3B,16u-diol-21-oic acid methyl ester,

(63) The 3-acetate of the ZO-[trans]-(4-methyl-pent-3'- enyl)-A -pregnadiene-3B,16B-diol-21-oic acid methyl ester,

(64) The 3-acetate of the ZO-[trans]-(4-methyl-pent-3'- enyl) -A -pregnadiene-3,B,16a-diol-2 l-oic acid methyl ester.

Example XIII 2 cc. of dihydropyrane were added to a solution of 1 g. of Compound No. 45 in 15cc. of benzene and about 1 cc. was distilled to remove moisture. 0.4 g. of p-toluenesulfonic acid were added to the cooled solution, which was then allowed to stand at room temperature for 4 days. The solution was washed with sodium carbonate and water, dried and evaporated. The residue was chromatographed on 15 g. of neutral alumina. Crystallization of the fractions eluted with hexane from pentane yielded the 3-acetate-16-tetrahydropyranylether of the 20-[cis]-methyl-A -pregnadiene-3,6,16a-diol 21 oic acid methyl ester (Cpd. No. 65).

A suspension of 1 g. of the latter compound in 60 cc. of methanol was treated with a solution of 1 g. of potassium carbonate in 6 cc. of water; the mixture was boiled under reflux for 1 hour and then cooled in ice, acidified with dilute hydrochloric acid and diluted with Water. The formed precipitate was collected and recrystallized from acetone-hexane to yield the 16-tetrahydropyranyl ether of 20-[cis]-methyl-A -pregnadiene-3fi,16a-diol- 21-oic acid (Cpd. No. 66).

A solution of 0.9 g. of Compound No. 66 in cc. of toluene and 20 cc. of cyclohexanone was dried by distilling off 10 cc. of the solvent. A solution of 1 g. of aluminum isopropoxide dissolved in 7 cc. of anhydrous toluene was then added and the mixture was refluxed for 45 minutes; 4 cc. of acetic acid were added and the solvents removed by steam distillation. The product was extracted several times with ethyl acetate and the organic extracts washed with 5% hydrochloric acid solution, water, 10% sodium carbonate solution and water until neutral, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetone-hexane atforded the 16-tetrahydropyranylether of 20-[cis].-methyl-A -pregnadien-16a-ol-3-one-21-oic acid (Cpd. No. 67). i

To a solution of the latter compound in 30 cc. of acetic acid was added 0.5 cc. of 2 N hydrochloric acid. After 5 hours at room temperature, ice water was added and the product extracted with methylene chloride. The

Y extract was washed to neutral, dried over anhydrous 11 tion from acetone-hexane yielded -[cis]-methyl-A pregnadien-l6a-ol-3-one-2l-oic acid (Cpd. No. 68).

The Compounds Nos. 46 to 64, inclusive, were treated following the above procedures, thus affording successively the corresponding 16-tetrahydropyranylethers, the corresponding 16-tetrahydropyranylethers of the free 3 8- ol-2l-oic acids, the corresponding 16-tetrahydropyrany1- ethers of the A -3-keto-21-oic acids and finally the following respective compounds:

Cpd. No.:

(69) ZO-[cis]-methyl-A -pregnadien-165-01 3 one- 21-oic acid,

() ZO-[trans]-methyl-A -pregnadien-l6,B-ol-3-one- 2l-oic acid,

(71 2O-[trans]-methyl-A -pregnadien-16a-ol-3-one- 21-oic acid,

(72) 20-[cis]ethyl-A -pregnadien-166-01 3 one- 21-oic acid,

(73) ZO-[cis]ethyl-A -pregnadienrl6a-ol 3 one- 21-oic acid,

(74) 20-[trans]ethyl-A -pregnadien-l6B-ol-3 one- 21-oic acid,

(75) 20-[trans]ethyl-A -pregnadien-l 6a-0l-3 one- 21-0ic acid,

(76) ZO-[cis]-isohexyl-A -pregnadien-l6fi-ol-3 one- 21-oic acid,

(77) 20-[cis]-isoheXyl-A -pregnadien-16a-ol-3-one- 21-oic acid,

(78) 20-[trans]-isoheXy1-A -pregnadien-16B ol 3- one-21-oic acid,

(79) 20-[transj-isohexyl-A -pregnadien-Ma ol 3- one21-oic acid,

(80) 20-[cis]-viny1-A -pregnadien-l6,8 o1 3 one- 21-oic acid, 9

(81) 2O-[cis}-vinyl-A -pregnadien-16oc-ol 3 one- 2l-oic acid,

(82) 20-[trans]-vinyl-A -pregnadien-16191-01-3 one- 21-0ic acid,

21-oic acid,

(84) 20-[cis]-(4'-methyl-pent-3-enyl-)A pregnadien-16fi-o1-3-one-21-oic acid,

(85) 20-[cis]-(4-methyl-pent-3'enyl)-A pregnadien-16ot-ol-3-one-21-oic acid,

(87') 20- [trans] (4'-methyl-pent-3 '-enyl) -A -pregnadien-16a-ol-3-one-2l-oic acid,

Example XIV A t-butanol solution containing 1.1 molar equivalents of methyl iodide was added dropwise to a boiling solution of 2 g. of Compound No. 68 in 30 cc. of t-butanol containing 1.1 g. of potassium over a period of 2.5 hours. It was then refluxed for a further 0.5 hour, cooled to room temperature, the bulk of the solvent was removed under vacuum and the product was precipitated with water. Isolation with ether gave a product which was adsorbed from 100 cc. of benzene onto 100 g. of alumina. Elution, followed by recrystallization from acetone-hexane afforded 4,20-[cis]-dimetl1yl-A -pregnadien-16aol-3-one-21-oic acid (Cpd. No. 88).

The Compounds Nos. 69 to 87, inclusive, were treated by the same procedure, thus yielding respectively:

Cpd. No.2

(93) 4-methyl-20- [cis] ethyl-A -pregnadien-16aol-3-one-2l-oic acid,

(94) 4-methyl-20-[trans] -ethyl-A -pregnadien- 16,8-ol-3-one-21-oic acid,

(95) 4-rnethyl-20- [trans] ethyl-A -pregnadien- 160c-Ol-3-0116-21-01C acid,

( 96) 4-methyl-20- [cis] -isoheXyl-A=- "(20) -pregnadien- 16Bol-3-one 21-oic acid,

(97) 4-methyl-20- [cis] -isoheXyl-A -pregnadien- 16cz-Ol-3-O116-21-0i6 acid,

(99) 4-methyl-20-[trans] -isoheXyl-A -pregnadien- 16a-0l-3-one-21-0ic acid,

( 100) 4-methyl-20- [cis] -vinyl-A -pregnadien- 16l9-ol-3-one-21-oic acid,

(101) 4-methyl-2O-[cis]-vinyl-A -pregnadien- 16a-ol-3-one-2 l-oic acid,

( 102) 4-methyl-20- [trans] vinyl-M -pregnadien- 16 fi-ol-3-one-2 l-oic acid,

(194) 4-methyl-20- cis] (4-1nethyl-pent-3 '-enyl M -pregn adien- 6,8-ol-3-one-2 l-oic acid,

(105) 4-methyl-2G- [cis] -(4'-metliyl-pent-3'-enyl) n -pregnadien-16a-ol-3-one-Z1-oic acid,

(106) 4-niethyl-20- [trans] 4'-methyl-pent-3 '-enyl A -pregnadien-16,9-ol-3-one-21-oic acid,

(107) 4-methyl-2 0- [trans] (4'-methyl-pent-3-enyl) A -pregnadien-16a-ol-3-one-2 l-oic acid,

Example XV A suspension of 0.5 g. of 5% palladium on carbon catalyst in 50 cc. of methanol was hydrogenated for 30 minutes. A solution 2 g. of Compound No. 88 in 200 cc. of methanol was added to the catalyst and stirred under a hydrogen atmosphere until the uptake of hydrogen was 1.1 molar equivalent. After removal of the catalyst by filtration the solution was evaporated and the crude residue was purified by crystallization from methylene-chloride-hexane, thus giving 45,20 [cis] dimethyl Alma) allopregnen 16cc ol 3 one 21 oic acid (Cpd. No. 108).

The Compounds Nos. 89 to 107, inclusive, were treated by the above procedure, thus yielding respectively:

Cpd. No.:

' (109) 45,20-[cis] -dimethyl-A -allopregnen- (1 19) 4fl-rnethyl-20- [trans] -is0heXyl-A -allopregnen- 16oc-Ol-3-0116-2l-Oi0 acid,

( 4fi-methyl-20- [cis] -vinyl-A -allo pregnen- 1613-01-3 -one-2 l-oic acid,

(121) 4,8-methyl-20- [cis] -vinyl-A -allopregnen- 16a-ol-3-one-21-oic acid,

(122) 4,8-methyl-20- [trans] -vinyl-A l i allopregnem 16fi-o1-3-one-21-oic acid,

(123) 4fi-methyl-20- [trans] -vinyl-A -allopregnenl6cz-0l-3-OD6-21-O1C acid,

( 124) 4/3-methyl-20- [cis] 4'-methyl-pcnt-3 -enyl A -allpregnen-16B-o1-3-one-2l-oic acid,

(125) 4,8-methyl-20- [cis] (4'-methyl-pent-3 -enyl) A -a1lopregnen-16a-o1-3-one-21-oic acid,

(126) 4B-methyl-20- [trans] (4'-mcthyl-pent-3-enyl) A -a1lopregnen-16/i-ol-3-one-21-oic acid,

(127) 4/3-methyl-20- [trans] (4'-methyl-pent-3 '-enyl) A -allopregnen-1 6C-Ol-3 -one-21-oic acid.

Example XVI 1 g. of Compound No. 108 was dissolved in 20 cc. of methanol containing 0.2 g. of sodium hydroxide and the mixture was kept for one and a half hours at room temperature, then poured into water acidified with hydrochloric cid and extracted with methylene chloride. Evaporation of the methylene chloride solution and crystallization of the residue from acetone-hexane yielded 4a,20- [cis]-dimethyl-n -allopregnen-16u-ol-3-one 21 0ic acid (Cpd. No. 128).

The Compounds Nos. 109 to 127, inclusive, were treated according to the latter procedure, thus affording respectively the following compounds:

Cpd. No:

(129) 4a,20-[cis]-dimethyl-A -allopregnen-16,8-01 3- 0ne-21-oic acid,

(130) 401,20[trans]-dimethyl-A -allopregnen-165 ol- 3-one-21-oic acid,

(131) 4u,20- [trans] -dimethyl-A -'1llopregnen-1601-01- 3-one-21-oic acid,

(132) 4-methy1-20-[cis]ethyl-A -allopregnen 16B- ol3-one-21-oic acid,

(133) 4a-methyl-20-[cis]ethyl-A -allopregnen 160col-3-one-2l-oic acid,

(134) 4a-methyl-20-[trans]-ethyl 11 allopregnen- 16fl-ol-3-one-21-oic acid,

(135) 4a-methyl-20-[transJ-ethyl A allopregnen 16a-Ol-3-OI16-21-01C acid,

(136) 4a-methyl-20-[cis] isohexyl A -allopregnen- 16,9-ol-3-one-21-oic acid,

(137) 4a'methyl-20-[cis]-isohexyl A -allopregnen 16u-ol-3-one-2l-oi0 acid,

(138) 4a-methyl-20-[trans] isohexyl-A -all0pregnen- 16B-ol-3-one-21-oic acid,

(139) 4a-methyl-20-[trans]-isohexyl-A allopregnen- 16oc-Ol-3-OI1-Zl-O1C acid,

(140) 4a methyl 20-[cis] -viny1- -allopregnen-16B- ol-3-one-21-oic acid,

(141) 4ot-methyl-20-[cis]-vinyl 11 allopregnen-laol-3-one-21-oic acid,

(142) 4a-methyl20-[trans]-viny1 Almo) allopregnen- 16 8-ol-3-one-21-oic acid,

(143) 4u-rnethyl-20-[trans]-vinyl A allopregnen- 16a-ol-3-one-21-oic acid,

( 144) 4a-methyl-20- [cis] (4-methyl-pent-3 '-cnyl) -A allopregnen-165-0l-3-one-2l-oic acid,

(145) 4a-methyl-20-[cis]-(4'-methyl pent 3'-enyl)- A -allopregnen-16u-ol-3-one-21-oic acid,

(146) 4a-rnethyl-20-[trans]-(4'-methyl pent 3'-enyl)- A -allopregnen-16B-o1-3-one-2l-oic acid,

(147) 4u-methyl-20-[trans]-(4'-methyl pent 3'-enyl)- A -allopregnen-16a-ol-3-one-2l-oic acid.

Example XVII The Compound No. 128 was treated according to EX- ample XII, thus yielding 4u,20-[cis]-dimethyl-A allopregnene-Zfl-16a-diol-21-oic acid (Cpd. No. 148).

The Compounds Nos. 129 to 147, inclusive, were treated following the same procedure, thus yielding respectively:

Cpd. No.:

(149) 4cz,20-[cis]-dimethy1A -al10pregnene 318,165-

dio1-21-oic acid,

(150) 4a,20-[trans] dimethyl A1790) allopregnene- 3 9, 16fi-diol-21-oic acid,

( 1i51) 4oz,20- [trans] -dimethyl-A -al1opregnene-3/8,16a-

diol-Zl-oic acid,

(152) 4a-methyl-20-[cis]-ethyl A allopregnene- 35,165-diol-2L0ic acid,

(153) 4a-methyl-20-[cis] ethyl A -allopregnene- 3,8,16oc-di0l-21-01C acid,

(154) 4a-methyl-20-[trans]-ethyl N all0pregnene 3,8,16fl-diol-21-oic acid,

(156) 4ot-methy1-20-[cis]-isohexyl-A allopregnene- 3 5,16,8-diol-21-oic acid,

(157) 4a-methyl-20-[cis]-isohexyl-A allopregnene- 3,6, 16u-diol-21-0ic acid,

( 158) 4a-methyl-20-[trans] -is0heXyl-A -allopregnene- 35,16,8-diol-21-oic acid,

( 159) 4a-II161hy1-20- [trans] -isoheXyl-A -allopregnene- 3 5,16a-diol-21-0ic acid,

(160) 4a-methyl-20-[cisJ-vinyl A1790) allopregnene- 3p',16,8-diol-21-0ic acid,

(161) 4a-methyl-20-[cis]-vinyl A1790) allopregnene- 318, 16oc-diOl-2 1-oic acid,

(162) 4a-methyl-20-[trans]-vinyl-A allopregnene- 35,16,8-diol-21-oic acid,

(163) 4a-methyl-20-[trans] -vinyl 11 allopregnene- 313,16oc-diOl-Zl-Oi0 acid,

(164) 4a-methy1-20-[cis1-(4' methyl pent 3'-enyl)- A -allopregnene-3,8,16B-diol-21-oic acid,

(165) 4a-methyl-20-[cis]-(4'-methyl-pcnt 3 enyl)- A -allopregnene-3B, 1 60L-diO1-21-Ol6 acid,

(166) 4a-methyl-20-[trans] (4' methyl-pent-3'-eny1) A -allopregnene-3;8,16,8-diol-21-oic acid,

(167) 4a-methy1-20-[trans]-(4'-methyl-pent 3' enyl)- A -a11opregnene-3/3,16ot-dio1-21-oic acid.

Example XVIII A mixture of 1 g. of Compound No. 128, ca. 10 g. of non-pyrophoric Raney nickel (about 1 to 3 months old) and 125 cc. of ethanol was refluxed for 5 hours, cooled and filtered. The filtrate was evaporated to dryness and the residue chromato-graphed on 40 g. of alumina. Crystallization of the eluted fractions yielded 404,20-[Ci81- dimethyl A allopregnene 30,l6oc-diO1-21-01C acid (Cpd. No. 168).

The compounds Nos. 129 to 147, inclusive, were treated following the same procedure, thus furnishing respectively:

Cpd. No;

(181) 4a methyl--[cis]-vinyl-A -aIiopregnene-Bie,

16a-diol-21-oic acid,

(182) 4a methyl-ZO-[trans] -vinyl-A -allopregnene- 3a,16;8-diol-21-oic acid,

(183) c methyl 20-[trans1-vinyl-A allopregnene- 3a,l6ot-diol-21-oic acid,

(184) 4a methyl 20 [cis]-(4'-methyl-pent-3-enyl)- A -allopregnene-3a,l6fl-diol-2l-oic acid,

(187) 4d methyl 20-[trans]-(4-methyl-pent-3-enyl)- A -allopregnene-3a,16u-diol-21-oic acid.

Example XIX A mixture of 1 g. of Compound No. 128, 4 cc. of pyridine and 2 cc. of caproic anhydride was kept at room temperature overnight, poured into ice Water, the formed precipitate was filtered, Washed with water and dried. Crystallization from acetone-hexane gave the 16-caproate of 404,20 [cis] dimethyl A -allopregnen-16u-ol-3- one-21-oic acid (Cpd. No. 188).

The Compounds Nos. 148 and 168 were treated by the above procedure, thus yielding respectively: the dicaproate of 40,20 [cis] dimethyl A -all0pregnene-3fi,16adio-l-Zl-oic acid (Cpd. No. 189) and the dicaproate of 4:1,20 [cis]-dimethyl-A -allopregnene-3a,l6a-diol-2loic-acid (Cpd. No. 190).

The Compounds Nos. 129 through 147, inclusive, were treated by the same procedure and gave the corresponding l6-caproates.

Upon treatment of the Compound Nos. 149 through 167, inclusive and 169 through 187, inclusive, by the same procedure, there were obtained the corresponding 3,16- dicaproates.

Example XX Example XXI The Compounds Nos. 128, 148 and 168 were treated according to Example VIII, thus yielding respectively:

Cpd. No.:

(191) 4a,20 [cis] dimethyl-A -allopregnen-16a-ol- 3-one-21-oic acid methyl ester,

(192) 4:1,20 [cis]-dimethyl-A -allopregnenedfid6ediol-Zl-oic acid methyl ester,

(193) 40,20 [cis]-dimethyl-A -allopregnene-3 160;-

d-iol-Zl-oic acid methyl ester.

When treating the Compounds Nos. 129 to 147, inclusive, 149 to 167, inclusive and 169 to 190, inclusive, there were obtained the corresponding methyl esters.

Example XXII A solution of 1 g. of Compound No. 128 in cc. of ethanol was neutralized with a 0.5 N solution of sodium hydroxide in ethanol. The mixture was. evaporated to dryness under vacuum and the residue recrystallized from ethanol-Water, thus yielding the sodium salt of 401,20- [cis] dimethyl A allopregnen-l6ot-ol-3-one-21 oic acid (Cpd. No. 194).

The Compounds Nos. 129 to 190, inclusive, were.

treated by the same procedure, thus affording respectively:

Cpd. No.:

(195) The sodium salt of 4a,20-[cis] dimethyI-A allopregnen -l613-'ol-3aone 21-oic acid,

(196) The sodium salt of 404,20-[transl-dimethyl-A allopregnen-16,8-ol-3-one-2l-oic acid,

(197) The sodium salt of 41,20-[trans]-dimethyl-A allopregnen-16a-ol-3-one-21-oic acid,

(198) The sodium salt of 4ot-methyl 20- [cis] ethyl- A -allopregnen-16fi-ol-3-one-21-oic acid,

(199) The sodium salt of 40a methyl 20 [cis] ethyl- A -allopregnen-l6oc-ol-3-one-2l-oic acid,

(200) The sodium salt of 4a-methyl-20-[transJ-ethyl- A -allopregnen-16/30l-3-0ne-2l-oic acid,

(201) The sodium salt of 4a-methyl-20-[trans]-ethyl- A -allopregnen-16ix-ol-3-one-2l-oic acid,

(202) The sodium salt of 4oc-methyl-20-[cis1 -isohcxyl- N -allopregnen-16B-ol-3-one-2l-oic acid,

(203) The sodium salt of 4a-methyl-20-[cis]-isohexyl- A -allopregnen-16ot-ol-3-one-21-oic acid,

(204) The sodium salt of 4ct-methyl-20-[transl-isohexyl- A -allopregnen-16,6ol-3-one-21-oic acid,

(205) The sodium salt of 4a-methyl-20-[transl-isohexyl- A -allopregnen-16ot-ol-3-one-2l-oic acid,

(206) The sodium salt of 4a methyl 20 [cis] vinyl- A -allopregnen-16fi-ol-3-one-2l-oic acid,

(207) The sodium salt of 40: methyl 20 [cis] -vinyl- A -allopregnen-l6ot-ol-3-one-2l-oic acid,

(208) The sodium salt of 4ot-methyl-20-[trans]-vinyl- A -all0pregnen-16,6-01-3-one-21-oic acid,

(209) The sodium salt of 4ot-methyl-20-[trans]-vinyl- A" -allopregnen-16a-ol-3-one-21-oic acid,

(210) The sodium salt of 4a-methyl-2-0-[cis]-(4'-methylpent-3-enyl)-A allopregnen 16/3 ol 3-one-21- oic acid,

(211) The sodium salt of 4u-rnethyl-20-[cis]-(4-methylpent-3'-enyl)-A allopregnen 16a ol 3-0ne-2 loic acid,

(212) The sodium salt of 4a. methyl 20 [trans] (4- methyl-pent-3' enyl) A allopregnen 1613 ol- 3-one 21-oic acid,

(213) The sodium salt of 40: methyl 20 [trans] (4- methyl-pent-3-enyl)-A allopregnen 16oz. ol 3- one-Zl-oic acid,

(214) The sodium salt of 401,20-[cis]-dimethyl-A allopregnene-3fl,16a-diol-21-oic acid, v (215) The sodium salt of 4m,20-[cis]-dimethyl-A allopregnene-3B,16 8-diol-21-oic acid, (216) The sodium salt of 4a,20-[trans]-dimethyl-A allopregnene-313,16;8-dio1-2l-oic acid,

(217) The sodium salt of 4a,.20-[trans]-dimethyl-A allopregnene-BBJ6a-diol-21-oic acid,

(218) The sodium salt of 40: methyl 20 [cis] ethyl A -allopregnene-3;3,16,3-diol-21-oic acid,

(219) The sodium salt of 4a -methyl 20 [cis] ethyl- A -allopregnene-3fl,16e-diol-21-oic acid,

(220) The sodium salt of 4ix-methyl-20-[transl-ethyl- A !(20)-allopregnene-3B,16,8-diol-2l-oic acid,-

(221) The sodium salt of 4a-methyl-20-[trans]-ethyl- A -allopregnene-3B,16a-diol-2l-oic acid,

(222) The sodium salt of 4oc-rnethyl-20-[cis]-isohexyl A -allopregnene-3fl,16,8-diol-21-oic acid,

(223) The sodium salt of 4et-methyl-20-[cis]-isohexyl- A -allopregnene-3p,16a-diol-21-oic acid,

(224) The sodium salt of 4a-methyl-20-[trans]-isohexyl- A -allopregnene-3fi,16fl-diol-2l-oic acid, I

(225) The sodium salt of 4a-methyl-20-[trans]-isohexyl- A -allopregnene-3p,l6a-diol-21-oic acid,

(226) The sodium salt of 40: methyl 20 [cis] -vinyl- A -allopregnene-3,6,16f3-di0l-2l-oic acid,

(227) The sodium salt of 40a methyl- 20 [cis] -vinyl- A -allopregnene-3{3,16ot-diol-21 oic acid,

(228) The sodium salt of 4oc-rnethyl-20-[trans]-vinyl- (229) The sodium salt of 4a-mcthyl-20-[transl-vinyl- A -al1OpI'gnIl6-3,8,1606-11101-2l-OlC acid, (230) The sodium salt of 4a-mcthyl-20-[cis]-(4'-methylpent-3'-enyl)-A allopregnene 35,16,8-diol-21-oic acid, I V

(231) The sodium salt of 4u-methyl-2'0-[cis]-(4'-methyl pent-3'-enyl) -A allopregnene 3,13,16u-dio1-21-oic acid,

(232) The sodium salt of 4a methyl 20 [trans] (4- methyl-pent-3-enyl) -A allopregnene-3,l9,1618-diol 2l-oic acid,

(233) The sodium salt of 40a methyl 2O [trans] (4'- rnethyl-pent-3'-enyl)-A allopregnene-3fi,l6a-diol- 21-oic acid,

(234) The sodium salt of 4u,20-[CiS]-dim6thyl-A 'allopregnene-3rx,16u-dio1-21-oic acid,

(235) The sodium salt of 4a,20-[cis]-dimethyl-A allopregnene-3a,16B-diol-21-oic acid,

(236) The sodium salt of 404,20-[trans]-dimethyl-A allopregnene-3a,16,8-diol-21-oio acid,

(237) The sodium salt of 40:,20-[trans]-dimethyl-A allopregnene-3a,16a-diol-21-oic acid,

(238) The sodium salt of 4a -methyl 20- [cis] ethyl- A -allopregnene-3a,16B-diol-21-oic acid,

(239) The sodium salt of 40a methyl 20 [cis] ethyl- A -allopregnene-3a,16a-diol-21-oic acid,

(240) The sodium salt of 4a-methyl-20- [trans]-ethyl- A -allopregnene-3a,l6fi-diol-2l-oic acid,

(241) The sodium salt of 4a-methyl-20-[trans]-ethyl- A -allopregnene-3a,16a-diol-21-oic acid,

(242) The sodium salt of 4a-methyl-20-[cis]-isohexyl- A -allopregnene-3a,l6 8-diol-2l-oic acid,

(243) The sodium salt of 4a-methyl-20- [cis]-isohexyl- A -allopregnene-3a,l6a-diol-2l-oic acid,

(244) The sodium salt of 4u-rnethyl-20-[trans] -isoheXyl- A -allopregnene-3a,16fi-diol-21-oic acid,

(245) The sodium salt of 4u-methyl-20-[trans1-isohexyl- A -'1l1opregnene3u,16a-diol-21-oic acid,

(246) The sodium salt of 4a methyl 20 [cis] vinyl- A -a lopregnene-3a,16/3-diol-21-oic acid,

(247) The sodium salt of 4a methyl- 20- [cis] vinyl- A -allopregnene-3a,16a-diol-2l-oic acid,

(248) The sodium salt of 4rx-methy1-20-[trans]-vinyl- A -allopregnene-3a,16,8-diol-2l-oic acid,

(249) The sodium salt of 4rx-methyl-20-[trans1-vinyl- A -allopregnene-3a,16a-diol-21-oic acid,

(250) The sodium salt of 4or-methyl-20-[cis]-(4'-methylpent-3'-enyl)-A allopregnene 3u,16fi-diol-21-oic acid,

(251) The sodium salt of 4a-rnethyl-20-[cis]-(4'-methylpent-3'-enyl)-A allopregnene 3a,l6u-diol-21-oic acid,

(252) The sodium salt of 40: methyl 20 [trans] (4'- rnethyl-pent-3-enyl)A allopregnene-3u,16fi-diol- 2l-oic acid,

(253) The sodium salt of 40a methyl 2O [trans] (4'- methyl-pent-3-enyl)-A allopregnene-3a,l6u-diol- 2l-oic acid,

(254) The sodium salt of the lfi-caproate of 4cc,20-[ClS] dimethyl-A" -allopregnen-16a-ol-3-one-21-oie acid, (255) The sodium salt of the dicaproate of 4a,20-[CiS]- dimethyl-A" -allopregenefi,16a-diol-21-oic acid, (256) The sodium salt of the dicaproate of 4oc,20-[CiS]- dimethyl-A -allopregnene-3a,16a-diol-21-oic acid,

Example XXIII The Compound No. 128 was treated according to EX- ample XXII, except that potassium hydroxide was used instead of sodium hydroxide thus yielding: The potassium salt of 4u,2O-[cis]-dimethyl-A -allopregnen-16aol-3-one-2l-oic acid (Cpd. No. 257).

Upon treatment of Compounds Nos. 129 to 190, inclusive, by the same procedure, there were obtained the corresponding potassium salts.

Example XXIV The Compound No. 68 was treated according to Example XV, thus giving 20-[cis]-methyl-A -allopregnenl6a-ol-3-one-2l-oic acid (Cpd. No. 258).

Upon treatment of the Compounds Nos. 69 to 87, in-

. 18 elusive, by the same procedure, there were obtained the corresponding A -all0pregnene derivatives.

We claim: 1. A compound represented by the formula:

wherein R is selected from the group consisting of hydrogen and an acyl group containing less than 12 carbon atoms; R is selected from the group consisting of hydrogen, a lower alkyl group and an alkali metal; R is an aliphatic hydrocarbon radical containing from 1 to 8 carbon atoms, inclusive; and R is selected from the group consisting of a-hydroxyl, fl-hydroxyl, i-tetrahydropynanyl ethers thereof, and a keto group.

2. A compound represented by the formula:

o a double bond at the 4,5-positi0n.

3. A compound represented by the formula:

may

wherein R is selected from the group consisting of hydrogen and an acyl group containing less than 12 carbon atoms; R is selected from the group consisting of hydrogen, a lower alkyl group and an alkali metal; R is an aliphatic hydrocarbon radical containing from 1 to 8 carbon atoms, inclusive; R is selected from the group con sisting of hydrogen and an acyl group containing less than 12 carbon atoms, and R is a lower alkyl group.

4-. 4a,2 0-dimethyl-A -allopregnene-3,16 diol 21- oic acid.

5. An alkali metal salt of 4a,20-dimethyl-A -allopregnene-3,16-diol-21-oic acid.

6. 4a-methyl-20-ethyl-A -allopregnene 3,16 diol- 21-oic acid.

7. An alkali metal salt of 4a-methyl-2O-ethyl-A allopregnene-3,16-diol-21-oic acid.

8. 4ocIn$thYl-ZO-i80h6XYl-A allopregnene 3,16- diol-21-oic acid.

9. An alkali metal salt of 4a-methyl-20-isohexyl-A allopregnene-3,16-diol-21-oic acid.

10. 4u-methy1-2O-vinyl-A -a1l0pregnene-3,16 diol- 21-0ic acid.

11. An alkali metal salt of 4oc-methyl-2O-vinyl-A allopregnene-3,16-diol-21-oic acid.

12. 4a-methyl-20-(4-methylpent 3 enyl) A allopregnene-3,16-diol-2l-oic acid.

13. An alkali metal salt of 4a-methyl-20-(4- ethylpent-3 -enyl)-A -allopregnene-3,16-diol-21-0ic acid.

14. 40,20-[cis]-dimethyl-A -all0pregnene 304,160:- diol-Zl-oic acid.

15. An alkali metal salt of -4u,20-[cisl-dimethyl- A -allopregnene ila,l6m-diol-21-0ic acid.

16. The sodium salt of 4a,2()-[cisLdimethyl-A allopregnene-3a,16a-diol-2l-oic acid.

17. 4a-methyl-20- [cis]-etl1yl-A allopregnene 30c, 16a-diOl-21-0i6 acid.

18. 4-a-methyl-20-[cisl-isohexyl A allopregnene- 3u,16a-di0l-21-oic acid.

19. 4a-methyl-20-[cisl-vinyl-A -allopre nene 30c, 16a-di0l-21-0ic acid.

20. 4a-methyl-20-[cis] -(4-methylpent-3'-enyl) -A allopregnene-3a,16a-diol-21-oic acid.

No references cited. 

3. A COMPOUND REPRESENTED BY THE FORMULA: 